This grant application represents a proposed career development and research plan designed to accomplish my long-term career goals and my short-term training and research objectives. My long-term goal is to establish myself as an independent PI with a research program focused on developing effective treatment strategies for patients with diseases of aging. My training objectives are to refine my skills in clinical research methodology and ethics, refine my clinical expertise in evaluating patients with diseases of aging, develop expertise in PET imaging research, gain expertise in MRI analysis, learn to integrate biomarker analysis into clinical research, build a foundation in statistical analysis, and improve my grant writing skills. My research objectives are to determine 1) how inflammation and tau each relate to amyloidosis, neurodegeneration, and cognition, and 2) the spatial relationship among inflammation, tau, and amyloid. These objectives are designed to address an important knowledge gap in AD research. There is a critical need to determine how inflammation and tau develop in relation to amyloid deposition, neurodegeneration, and cognitive impairment and how they correlate with each other. My central hypothesis is that inflammation and tau increase in AD in a spatially related manner that is more closely associated with cognitive decline and brain atrophy than is amyloid burden. My preliminary clinical PET data suggests that inflammation is greater in AD than MCI and increases longitudinally, particularly in medial temporal cortex. This spatial and temporal progression is similar to that in autopsy studies that show tau pathology starts in medial temporal cortex and increases with degree of cognitive decline in AD. My rationale is that once it is known how inflammation and tau relate to risk of progression to AD, measuring these factors with PET can predict decline and serve as a biomarker for novel therapeutics. I will test my central hypothesis by performing inflammation and tau PET imaging in individuals with distinct clinical and biomarker profiles that define four different categories of cognitive aging: 1) Amyloid-positive elders who meet clinical criteria for amnestic MCI or mild AD (clinical AD group), 2) amyloid-positive elders without impairment (preclinical AD group), 3) amyloid-negative elders without impairment (normal aging group), and 4) amyloid-negative elders who meet clinical criteria for amnestic MCI or mild AD (suspected non-AD pathophysiology group).
The specific aims are: 1) Determine the extent of inflammation and tau burden in different categories of cognitive aging. I postulate that within medial temporal, lateral temporal, and parietal regions a step-wise pattern will exist such that amyloid-positive elders with impairment will have greater inflammation and tau burden than amyloid- positive elders who are cognitively normal, who in turn will have greater inflammation and tau than amyloid- negative elders without cognitive impairment. Because I predict impairment and amyloid status to have an additive effect on inflammation, I hypothesize that amyloid-negative elders with impairment will have greater inflammation than cognitive controls but less inflammation than amyloid-positive elders with impairment. I also postulate that inflammation and tau burden measured with PET will correlate with clinical severity, brain atrophy, and CSF biomarkers for inflammation and tau. 2) Determine the spatial relationship between inflammation, tau, and amyloid. My working hypothesis is that inflammation and tau will correlate in a regionally dependent manner that is spatially distinct from amyloid. My approach is innovative in that it uses an improved radioligand for inflammation and will be the first study, to my knowledge, to combine inflammation and tau PET imaging in the same subjects. This contribution will be significant because it is the first step in a continuu of research that is expected to lead to development of neuroimaging strategies to predict future cognitive decline in elderly individuals and inform pharmacological studies targeting inflammation and tau pathology in AD. My environment is uniquely suited to maximize the chance of successfully completing the above training and research objectives. Through my appointment at the Taub Institute at Columbia University Medical Center and the collaborations established in this application, I will have sufficient resources to support my career development and research plan, including PET radiopharmaceutical production, imaging, subject recruitment, and all necessary laboratory analyses. I have secured commitment of institutional support from my Chairman, my advisory committee, and necessary collaborators.
The proposed research is relevant to public health because determining the relationship between inflammation and tau pathology in Alzheimer's disease is expected to inform future strategies to predict and prevent progression to dementia. Thus, the proposed research is relevant to the NIA's mission that pertains to developing fundamental knowledge that will reduce the burden of Alzheimer's disease on society.
| Kreisl, William C; Henter, Ioline D; Innis, Robert B (2018) Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia. Adv Pharmacol 82:163-185 |
